Don't eat me/eat me signals as a novel strategy in cancer immunotherapy

Khalaji, Amirreza; Yancheshmeh, Fatereh Baharlouei; Farham, Fatemeh; Khorram, Arya; Sheshbolouki, Shiva; Zokaei, Maryam; Vatankhah, Fatemeh; Soleymani-Goloujeh, Mehdi

doi:10.1016/j.heliyon.2023.e20507

Cited by 9 publications

(3 citation statements)

References 124 publications

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“…It remains to be seen whether this combination will prove effective for melanoma in vivo , however other solid tumor models have demonstrated success with pairing αCD47 strategies with CAR-Ms both in vitro and in vivo (12,24,25,60). Future approaches to improve phagocytosis include using activation domains more specific to the engulfment machinery such as the Rac2E62K mutation (19) and targeting additional “don’t eat me” signals (61). If sustained CAR-M persistence at the tumor is deemed to be critical for tumor growth control, then efforts to improve CAR-M survival such as overexpression of cytokines like M-CSF may be needed (62).…”

Section: Discussionmentioning

confidence: 99%

CSPG4-targeting CAR-macrophages inhibit melanoma growth

Greiner,

Xue,

Waddell

et al. 2024

Preprint

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Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematological malignancies but has been clinically less effective in solid tumors. Engineering macrophages with CARs has emerged as a promising approach to overcome some of the challenges faced by CAR-T cells due to the macrophage’s ability to easily infiltrate tumors, phagocytose their targets, and reprogram the immune response. We engineered CAR-macrophages (CAR-Ms) to target chondroitin sulfate proteoglycan 4 (CSPG4), an antigen expressed in melanoma, and several other solid tumors. CSPG4-targeting CAR-Ms exhibited specific phagocytosis of CSPG4-expressing melanoma cells. Combining CSPG4-targeting CAR-Ms with CD47 blocking antibodies synergistically enhanced CAR-M-mediated phagocytosis and effectively inhibited melanoma spheroid growth in 3D. Furthermore, CSPG4-targeting CAR-Ms inhibited melanoma tumor growth in mouse models. These results suggest that CSPG4-targeting CAR-M immunotherapy is a promising solid tumor immunotherapy approach for treating melanoma.STATEMENT OF SIGNIFICANCEWe engineered macrophages with CARs as an alternative approach for solid tumor treatment. CAR-macrophages (CAR-Ms) targeting CSPG4, an antigen expressed in melanoma and other solid tumors, phagocytosed melanoma cells and inhibited melanoma growthin vivo. Thus, CSPG4-targeting CAR-Ms may be a promising strategy to treat patients with CSPG4-expressing tumors.

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Section: Discussionmentioning

confidence: 99%

CSPG4-targeting CAR-macrophages inhibit melanoma growth

Greiner,

Xue,

Waddell

et al. 2024

Preprint

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“…Current pharmaceutical development focuses on structural modifications to reduce RBC toxicities as well as on providing additional pro-phagocytic signals to trigger the optimal anti-tumor effects of macrophages. 182 …”

Section: Inhibitory Checkpoints and Protein Familiesmentioning

confidence: 99%

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Yin,

Li,

Zhang

et al. 2024

Sig Transduct Target Ther

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Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

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“…Most of myeloid cell types associated with GBM tumors, including macrophages, microglia and dendritic cells, retain the capacity to carry out phagocytosis under certain conditions [35][36][37][38][39][40][41][42][43]. The current paradigm is that tumor cells experiencing oncogenic cellular stress express and presentation of "Eat Me" signals such as surface exposed calreticulin , High mobility group box 1 protein (HMGB1), phosphatidyl serine (PS) among others [44,45]. When these signals are detected by tissue macrophages, the result rapid and efficient phagocytosis of the tumor cell.…”

Section: Macrophage Phagocytosis Of Glioma Cellsmentioning

confidence: 99%

Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond

Afzal,

Bizink

et al. 2024

Preprint

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Glioblastoma multiforme (GBM) is one of the deadliest human cancers with very lim-ited treatment options available. The malignant behavior of GBM is manifest in a tu-mor which is highly invasive, resistant to standard cytotoxic chemotherapy and is strongly immunosuppressive. Immune checkpoint inhibitors have recently been in-troduced in the clinic and have yielded promising results in certain cancers. GBM however is largely refractory to these treatments. The immune checkpoint CD47 has recently gained attention as potential target for intervention as it conveys a “don’t eat me” signal to tumor associated macrophages via the inhibitory SIRP alpha protein. In preclinical models, administration of anti-CD47 monoclonal antibodies have shown impressive results with GBM and other tumor models. Several well characterized on-cogenic pathways have recently been shown to regulate CD47 expression in GBM cells and Glioma Stem cells (GSCs) include EGFR, beta catenin and LRIG2. Other macro-phage pathways involved in regulating phagocytosis including TREM2 and glycan binding proteins are discussed as well. Finally, Chimeric Antigen Receptor Macro-phages (CAR)-M could be leveraged for greatly enhancing phagocytosis of GBM and repolarization of the microenvironment in general. Here we comprehensively review the mechanisms that regulate about macrophage phagocytosis of GBM cells.

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Don't eat me/eat me signals as a novel strategy in cancer immunotherapy

Cited by 9 publications

References 124 publications

CSPG4-targeting CAR-macrophages inhibit melanoma growth

CSPG4-targeting CAR-macrophages inhibit melanoma growth

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond

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